Female reproductive cancers contributed substantially to mortality among women aged 35-60 years, according to a cohort study that analyzed data from 20 countries comprising more than six decades of mortality records.

The consistent excess in cancer mortality compared to men of the same age was primarily driven by breast and gynecologic cancers. Eliminating these female reproductive cancers would increase average female lifespan and expand the female to male survival gap by an estimated mean of 0.77 years (95% CI, 0.75-0.78), ranging from 0.51 years (95% CI, 0.50-0.52) in Japan to 0.96 years (95% CI, 0.92-1.00) in Ireland.

The analysis included 264.4 million deaths, of which 119.1 million occurred in women and 11.5 million (9.7%) were attributable to female reproductive cancers.

Abirami Sivapiragasam, MD, who was not involved with the research, characterized the study as “definitely an eye-opening one for many of us” and said, “Spreading the word about studies like this would be very important.”

I think there is still [room] to improve in educating our women in their thirties, forties, and fifties [about the importance of screening]. Many, many women actually associate cancer risk, primarily breast cancer risk, with older age, and they may not realize that breast cancer is one of the leading causes of cancer deaths in midlife women globally,” said Sivapiragasam, the director of medical oncology at the Hollings Cancer Center at the Medical University of South Carolina in Charleston, South Carolina.

The findings, which were published in JAMA Network Open, align with a noteworthy shift in the overall cancer burden toward young and middle-aged adults, especially women. One recent study found that cancer rates in women aged 50 years or younger are now 82% higher than those in men of the same age, up from a 51% difference in 2002. Another study echoed these findings, reporting the largest absolute increases in early-onset cancer incidence for breast, colorectal, kidney, and uterine cancers.

The new research suggests that more work is needed to prevent, detect, and treat female reproductive cancers, reported lead author Vladimir Canudas Romo, PhD, of The Australian National University in Canberra, Australia, and colleagues.

Why and How Was This Study Conducted?

“Females now expect to live longer than males in every country and region of the world,” the investigators wrote. “Evidence suggests that females generally benefit from an inherent advantage related to biological endowments, such as hormonal, autoimmune, and genetic factors. However, certain hormones, particularly estrogens, are key factors associated with the development and progression of hormone-dependent cancers in females, including breast, endometrial, and certain ovarian cancers.”

Most research in this area has focused on why men tend to have a shorter lifespan than women, whereas studies evaluating female lifespan are rare, Romo and colleagues noted.

This knowledge gap prompted the present study, which aimed to better understand how female reproductive cancers and other major causes of death affect mortality among women and how those impacts affect the known survival disparities between men and women.

The cohort study used population-level mortality data from 20 countries, including the US, in the Human Mortality and World Health Organization Mortality Databases spanning 1955-2020.

The primary outcome was the truncated cross-sectional average length of life, a measure of survival that incorporates long-term mortality patterns across birth cohorts rather than relying only on current life expectancy.

The investigators compared survival between women and men in each country and examined how differences varied by age and cause of death.

The female survival advantage ranged from 4.22 years (95% CI, 4.20-4.25) in Netherlands to 8.31 years (95% CI, 8.28-8.34) in Hungary. This advantage narrowed at ages 35-60 years due to excess cancer mortality among women, primarily driven by breast and gynecologic cancers.

What Factors Are Driving This Increased Risk Among Women in Midlife?

The authors of the present study suggested that the elevated risk for breast and gynecologic cancers during reproductive years is largely driven by sex hormones, whereas menopause has a protective effect.

“Without the onset of menopause, the incidence of female reproductive cancers at older ages would likely be substantially higher,” they wrote. “Thus, the elevated risk of breast and gynecological cancers during the reproductive years may be interpreted as a biological cost — or the price of reproduction.”

However, several outside experts suggested that the full picture is more complex and described opportunities for risk mitigation.

“While hormones may play a role in the propagation and risk of these cancers, they do not tell the whole story,” Sarah Taylor, MD, PhD, director of clinical research in gynecologic oncology at the University of Pittsburgh and UPMC Magee-Womens Hospital, both in Pittsburgh, told Medscape Medical News. “Each female-specific cancer has its own unique set of risk factors, environmental influences, and underlying disease biology.”

Taylor pointed out that over 99% of cervical cancers are linked to human papillomavirus, which can be mitigated by vaccination and screening. Other modifiable risk factors for female reproductive cancers include tobacco use, alcohol consumption, body weight, and diet, she added.

Jairam Krishnamurthy, MD, associate professor of medicine in the Division of Oncology at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, also emphasized the importance of lifestyle choices in reducing the risk for breast cancer.

“Studies have shown that when women exercise and introduce dietary modification, their weight is closer to their ideal body weight, and that has been shown to reduce the risk of developing breast cancer and recurrence of breast cancer,” Krishnamurthy said in an interview.

Sivapiragasam noted the importance of both lifestyle and environmental factors.

“We are seeing that more and more younger women are being diagnosed with breast cancer compared to the years before,” Sivapiragasam said in an interview. “So there is something definitely happening with environment and lifestyle changes.”

Beyond the influence of the lifestyle factors described above, Sivapiragasam noted that some women are choosing to breastfeed for a shorter time, which may increase the risk for breast cancer compared with those who nurse for a longer duration, as a study published in The Lancet suggests.

Environmental exposures, including endocrine-disrupting chemicals, may also be playing a role, she added.

Is Enough Being Done to Educate Women About Reproductive Cancers?

When asked if enough is being done to educate women in midlife about reproductive cancers and associated risks, the experts unanimously agreed that current efforts are falling short.

“No, there is not enough being done to adequately educate women in this age group about these risks,” Taylor said. “Education should come from trusted sources, particularly through one-on-one conversations with primary care physicians and ob/gyns, as well as through broader public agencies.”

“I’m not certain if [risk education] is really happening at the level that we would like for it to be,” Krishnamurthy said. He suggested that primary care doctors are likely in the best position to deliver this information.

Although Sivapiragasam agreed that primary care providers can play a key role, she emphasized the need for alternative outreach methods.

“Some of these young women in this age group may not have doctors; they may not have insurance,” Sivapiragasam said. She suggested that oncology societies and public health agencies leverage social media to more effectively reach such individuals, calling it a “very powerful tool” for public health education.

How Should Screening Protocols and Clinical Risk Stratification Change?

Beyond public health education, the experts also agreed that more work is needed to individualize screening for at-risk individuals.

For instance, Sivapiragasam said many patients remain unaware that specific personal risks, such as BRCA mutations, qualify them for screening at a younger age.

Krishnamurthy noted that guidance has shifted to encourage screening at a younger age, including the US Preventive Services Task Force recommendation to begin breast cancer screening starting at age 40; however, adjusting screening based on family history alone remains uncertain, requiring clinicians to calculate overall risk using tools such as the Gail model or the Tyrer-Cuzick scoring system.

In addition, he suggested that additional imaging may be needed for women with dense breasts, which can make it challenging for radiologists to differentiate normal from abnormal tissue.

“MRI in those cases serves as a tiebreaker to help us determine whether we missed anything on mammogram,” Krishnamurthy said.

Yet optimized screening protocols are meaningless if patients cannot access them.

“Current screening protocols are evidence-based, but at a systems level, significant barriers continue to limit equitable access to cancer prevention, screening, and treatment,” Taylor said.

She advocated for expanding outreach to uninsured and underserved populations and investing in strategies to provide care where individuals live.

Sivapiragasam shared a similar perspective, pointing out that younger women are often in the workforce or acting as the primary breadwinners for their families.

“If you look at the statistics of how many patients are going for mammograms, especially in this young age cohort, not very many are going,” she said. This demographic is particularly impacted by financial and time constraints, so the medical community must close these gaps to improve survival.

The study was supported by the Australian Research Council, the European Research Council, Leverhulme Trust, and the Australian National Health and Medical Research Council Investigator Fellowship. The investigators and outside experts reported having no conflicts of interest.